A liposomal etoposide with a sustained drug release effectively alleviated the therapy-related leukemia

Etoposide (VP16) can induce therapy-related leukemia, which is reported to occur less frequently with a prolonged dose schedule. Therefore, we hypothesized that nanocarriers could decrease the VP16-induced leukemogenesis by reducing the rate of VP16 exposure via a sustained drug release. To test our hypothesis, the VP16-loaded liposome with a slow drug release behavior was constructed by encapsulating a rapidly-cleaved VP16-maleimide conjugate into liposomes using a glutathione-gradient loading method, and its toxicities and in vivo antitumor efficacy were compared with free VP16 in the LLC lung cancer xenograft. It was found that the repeated injection of free VP16 induced severe splenomegaly, lymphocytosis, and extensive lymphocyte infiltration in various tissues, indicating a sign of VP16 therapy-related leukemia. By contrast, the liposomal VP16 not only remarkably alleviated the syndrome of leukemogenesis, but also exhibited significantly enhanced antitumor activity as compared with free VP16 at the same dose. These results highlighted that the liposomal VP16 having a sustained drug release could effectively decrease the toxicity of leukemogenesis, which provided a new warranty to develop liposomal VP16 as a safe alternative to the commercial VP16 injection.